HIV, Hyperlipidemia
Conditions
Keywords
HIV, Hyperlipidemia, Pharmacokinetics, Statins, Darunavir, Efavirenz, Pitavastatin
Brief summary
The main goal of this study is to determine how taking efavirenz affects the levels of pitavastatin in the bloodstream when both drugs are taken together and to see how darunavir with ritonavir affects the levels of pitavastatin in the bloodstream. Secondary goals are to see how taking pitavastatin affects the levels in the blood of efavirenz when both drugs are taken together and to see how taking pitavastatin affects the levels in the blood of darunavir.
Detailed description
HIV infected persons are at risk for coronary heart disease due to chronic inflammation associated with the virus itself, the side effects of the antiretroviral (ARV) therapies which can cause elevated cholesterol, and the risk factors such as smoking, high blood pressure and family history of heart disease. The most commonly prescribed ARVs for treatment of HIV are efavirenz and drugs in the protease inhibitor (PI) class such as darunavir with ritonavir. To treat elevated cholesterol in patients infected with HIV, guidelines recommend the use of statins (a class of lipid lowering drugs). PIs and efavirenz can increase the levels of some statins and reduce the levels of others in the bloodstream. Pitavastatin (Livalo) is a statin approved by the Food and Drug Administration (FDA) for the treatment of high cholesterol. In order to be able to use pitavastatin safely in HIV-infected patients taking either darunavir with ritonavir or efavirenz, it is important to study how taking pitavastatin with darunavir and ritonavir or pitavastatin with efavirenz affect the levels of each of these drugs in the bloodstream. Twenty-eight participants will be enrolled in one of two study arms: 14 in Arm A and 14 in Arm B. Arm A: Participants will start taking pitavastatin 2 mg tablets every night at bedtime. On day 4 participants will come in for a 14-hour pharmacokinetic (PK) overnight visit and will have about 9 tablespoons of blood drawn. Participants will return 12 hours after the last blood draw for a final blood draw. They will then stop taking pitavastatin. Participants will then start taking one efavirenz 600 mg tablet at bedtime. On day 14, participants will come in for a second 14-hour visit and will have about 9 tablespoons of blood drawn. They will return 12 hour after the last blood draw for a final blood draw. Participants will then start taking both pitavastatin and efavirenz at bedtime. On day 18, participants will come in for a third 14-hour PK visit and will have about 9 tablespoons of blood drawn. They will return 12 hour after the last blood draw for a final blood draw. They will then stop taking all study drugs and will either come in or receive a final phone call on day 25. Arm B: Participants will start taking one pitavastatin 2 mg tablet every morning. On day 4 participants will come in for a 14-hour pharmacokinetic (PK) daytime visit and will have about 9 tablespoons of blood drawn. Participants will return 12 hours after the last blood draw for a final blood draw. They will then stop taking pitavastatin. Participants will then start taking darunavir 400 mg tablets (2) and ritonavir 100 mg tablets (1) every morning. On day 14, participants will come in for a second 14-hour visit and will have about 9 tablespoons of blood drawn. They will return 12 hour after the last blood draw for a final blood draw. Participants will then start taking one pitavastatin 2mg tablet, two darunavir 400 mg tablets and one ritonavir 100 mg tablet. On day 18, participants will come in for a third 14-hour PK visit and will have about 9 tablespoons of blood drawn. They will return 12 hour after the last blood draw for a final blood draw. They will then stop taking all study drugs and will either come in or receive a final phone call on day 25.
Interventions
DRUGPitavastatin
Pitavastatin 2 mg tablets taken at bedtime in Arm A and in the morning in Arm B.
DRUGDarunavir
Darunavir 400 mg tablets x 2 taken daily in Arm B
DRUGRitonavir
Ritonavir 100 mg tablets taken daily in Arm B
DRUGEfavirenz
Efavirenz 600 mg tablets taken at bedtime in Arm A
Sponsors
New York City Health and Hospitals Corporation
Kowa Pharmaceuticals America, Inc.
University at Buffalo
NYU Langone Health
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
* Absence of HIV-1 infection as documented by any licensed ELISA test kit within 21 days prior to study entry. * Male or female aged 18-60 years. * Able and willing to provide informed consent. * All men and women of reproductive potential must practice adequate birth control to prevent pregnancy from start of the study until completion of the study. * Women of childbearing potential must have a negative serum or urine pregnancy test within 14 days prior to study entry and day of entry. * Hemoglobin \> 12.5 g/dL for men; \> 11.5 g/dL for women; * Absolute neutrophil count \>1,500 cells/mm3; * Platelet count \> 100,000 platelets/mm3; * AST (SGOT)/ALT (SGPT) \<1.5X ULN; * Creatinine \<1.5 X ULN * Subject is within 20% (+/-) of ideal body weight and must weigh at least 50 kg
Exclusion criteria
* Use of illicit drugs or alcohol which would interfere with the completion of this study. * Pregnancy or breast-feeding. * History of chronic illnesses such as hypertension, coronary artery disease, arthritis, diabetes, or any chronic gastrointestinal conditions which might interfere with drug absorption. * Any medical condition which, in the opinion of the investigator, would interfere with the subjects ability to participate in this protocol. * Use of prohibited protocol-specified drugs, prescription or over-the-counter within 14 days prior to study entry. * Participation in any investigational drug studies within 30 days prior to study entry.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC | 0 to 24 hours | 24-hour area under the curve (AUC) for pitavastatin when coadministered with efavirenz and with darunavir/ritonavir and 24-hour AUC for efavirenz or darunavir when coadministered with pitavastatin |
| GMR of 24- Hour AUC of Pitavastatin When Coadministered With Efavirenz or With Darunavir/Ritonavir Over 24 Hour AUC of Pitavastatin | 0 to 24 hours | Geometric Mean Ratio (GMR) of 24- Hour Area under the plasma drug concentration-time curve (AUC) of pitavastatin when coadministered with efavirenz or with darunavir/ritonavir over 24 Hour (AUC) of pitavastatin |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| GMR of Cmax of Pitavastatin When Coadministered With Efavirenz or With Darunavir/Ritonavir | Day 18 | Geometric Mean Ratio (GMR) of Cmax for pitavastatin with Efavirenz vs. alone and GMR of Cmax for pitavastatin with darunavir/ritonavir vs. alone was reported. |
Countries
United States
Participant flow
Recruitment details
Accrual began August 24, 2012 and ended January, 8, 2013. All study procedures took place at the NYU/Bellevue Clinical Trials Unit and NYU Clinical and Translational Science Institute.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: (Pitavastatin and Efavirenz) Subjects assigned to Arm A will receive pitavastatin 2 mg at bedtime and efavirenz 600 mg at bedtime. | 18 |
| Arm B: (Pitavastatin and Ritonavir-boosted Darunavir) Subjects assigned to Arm B will receive pitavastatin 2 mg daily and darunavir 800 mg with ritonavir 100 mg daily. | 16 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Withdrawal by Subject | 4 | 0 |
Baseline characteristics
| Characteristic | Arm A: (Pitavastatin and Efavirenz) | Arm B: (Pitavastatin and Ritonavir-boosted Darunavir) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 16 Participants | 34 Participants |
| Sex: Female, Male Female | 8 Participants | 7 Participants | 15 Participants |
| Sex: Female, Male Male | 10 Participants | 9 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 14 / 18 | 7 / 16 |
| serious Total, serious adverse events | 0 / 18 | 0 / 16 |
Outcome results
Primary
AUC
24-hour area under the curve (AUC) for pitavastatin when coadministered with efavirenz and with darunavir/ritonavir and 24-hour AUC for efavirenz or darunavir when coadministered with pitavastatin
Time frame: 0 to 24 hours
Population: Subjects who completed all visits
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A: (Pitavastatin and Efavirenz) | AUC | 85.3 ng*hr/mL | Standard Deviation 5.72 |
| Arm B: (Pitavastatin and Darunavir) | AUC | 62.8 ng*hr/mL | Standard Deviation 6.24 |
Primary
GMR of 24- Hour AUC of Pitavastatin When Coadministered With Efavirenz or With Darunavir/Ritonavir Over 24 Hour AUC of Pitavastatin
Geometric Mean Ratio (GMR) of 24- Hour Area under the plasma drug concentration-time curve (AUC) of pitavastatin when coadministered with efavirenz or with darunavir/ritonavir over 24 Hour (AUC) of pitavastatin
Time frame: 0 to 24 hours
Population: Subjects who completed all visits
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Arm A: (Pitavastatin and Efavirenz) | GMR of 24- Hour AUC of Pitavastatin When Coadministered With Efavirenz or With Darunavir/Ritonavir Over 24 Hour AUC of Pitavastatin | GMR of Pitavastatin with (EFV or DRV)/Pitavastatin | .89 Ratio |
| Arm A: (Pitavastatin and Efavirenz) | GMR of 24- Hour AUC of Pitavastatin When Coadministered With Efavirenz or With Darunavir/Ritonavir Over 24 Hour AUC of Pitavastatin | GMR of (EFV or DRV) with Pitavastatin/(EFV or DRV) | .90 Ratio |
| Arm B: (Pitavastatin and Darunavir) | GMR of 24- Hour AUC of Pitavastatin When Coadministered With Efavirenz or With Darunavir/Ritonavir Over 24 Hour AUC of Pitavastatin | GMR of Pitavastatin with (EFV or DRV)/Pitavastatin | .91 Ratio |
| Arm B: (Pitavastatin and Darunavir) | GMR of 24- Hour AUC of Pitavastatin When Coadministered With Efavirenz or With Darunavir/Ritonavir Over 24 Hour AUC of Pitavastatin | GMR of (EFV or DRV) with Pitavastatin/(EFV or DRV) | 1.08 Ratio |
Secondary
GMR of Cmax of Pitavastatin When Coadministered With Efavirenz or With Darunavir/Ritonavir
Geometric Mean Ratio (GMR) of Cmax for pitavastatin with Efavirenz vs. alone and GMR of Cmax for pitavastatin with darunavir/ritonavir vs. alone was reported.
Time frame: Day 18
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Arm A: (Pitavastatin and Efavirenz) | GMR of Cmax of Pitavastatin When Coadministered With Efavirenz or With Darunavir/Ritonavir | 1.20 ng/mL |
| Arm B: (Pitavastatin and Darunavir) | GMR of Cmax of Pitavastatin When Coadministered With Efavirenz or With Darunavir/Ritonavir | 0.93 ng/mL |